1. Technical Field of the Invention
The present invention relates to a novel process for preparing camptothecin useful as a starting material for irinotecan hydrochloride and various camptothecin derivatives as anti-tumor agents.
2. Description of the Prior Art
Camptothecin (hereinafter referred to CPT) is a pentacyclic alkaloid which is isolated from natural materials such as Camtotheca acuminata Nyssaceae of Chinese origin, and various kinds of useful semi-synthetic derivatives with anti-tumor activities prepared from this as a starting material have been provided by the exploratory researches of the present inventors (see for example, JP, A, 1-186892; JP, A, 1-131179; JP, A, 8-73461; JP, A, 11-140085 and others).
7-Ethyl-10-piperidinopiperidinocarbonyloxycamptothecin (hereinafter referred to CPT-11) is a compound with high anti-tumor activity and low toxicity, and is now broadly sold as an anti-tumor agent (general name; irinotecan hydrochloride). Further, among CPT-11 analogues, there are many known to have similar anti-tumor effect.
However, owing to an extremely low amount of CPT obtained from natural materials such as Camtotheca acuminata Nyssaceae, it is anticipated that a sufficient supply of CPT will become difficult, despite the on going a measure for sufficient providing starting materials, such as afforestation, to catch up the increased demand for useful derivatives, such as CPT-11, and the like. Although the total syntheses have also been examined, because of many problems in terms of equipments, yields and costs and the like, the present situation is that it has yet to be into practical use.
Accordingly, it is the object of the invention to produce CPT, which is a starting compound of irinotecan hydrochloride and various camptothecin derivatives, at a low cost and with ease.
During the extensive researches made to solve the above problems, the inventors focused their attention on the so far discarded CPT analogues contained in natural materials such as Camtotheca acuminata Nyssaceae and then investigated that 9-methoxycamptothecin (hereinafter referred to 9-MC) had been obtained, unexpectedly, as a by-product of the CPT production in a considerable amount. As a starting material and to supply CPT steadily as a result of continuing research to utilize this further, the inventors found out means to prepare CPT, easily and efficiently from 9-MC and thus accomplished the invention.
Accordingly, the invention relates to a process for preparing camptothecin, characterized in that it comprises the following steps (a) and (b);
(a) the step to hydrolyze 9-methoxycamptothecin or a natural material containing 9-methoxycamptothecin;
(b) the step to convert 9-hydroxycamptothecin obtained in the step (a) into camptothecin by 9-O-perfluoro-lower-alkylsulfonylation or 9-O-phenyltetrazolylation, followed by hydrogenolysis.
Further, the invention relates to the above process, characterized in that, in the step (b), 9-hydroxycamptothecin is subjected to 9-O-trifluoromethanesulfonylation.
Furthermore, the invention relates to the process for preparing the above camptothecin, wherein 9-hydroxycamptothecin is the 20(S) isomer and camptothecin is 20(S)-camptothecin.
In the invention, 9-MC as the starting compound of CPT, can be used are those isolated and purified from various natural materials, those chemically converted from analogous compounds, or natural materials containing 9-MC themselves. Illustrative of the natural materials containing 9-MC are, for example, Camtotheca acuminata Nyssaceae, Nothapodytes foetida, Ervatamia heyneana, Ophiorrhiza japonica, though it is preferred that Nothapodytes foetida is used, due to its high content of 9-MC, particularly in Nothapodytes foetida. In case these natural materials are used, first they are untreated, or subjected to a treatment such as cutting and crushing, followed by extraction with an organic solvent such as methanol, ethanol, acetone, ethyl acetate, chloroform-methanol mixture and dichloromethane-methanol mixture. Thusxe2x80x94obtained extract is dried and may be used as it is, or the one appropriately purified by means of column chromatography, recrystallization or reprecipitation may be used.
In the invention, 9-MC or a natural material containing 9-MC is first converted to 9-hydroxycamptothecin hereinafter referred to xe2x80x9c9-HCxe2x80x9d by hydrolysis. Methods for conversion include a method to treat with iodotrimethylsilane in quinoline, chloroform or the like, a method to heat with sodium ethylmercaptan, potassium thiophenoxide, sodium thiocresolate or the like using dimethylformamide as a solvent, a method to heat with sodium cyanide in dimethyl sulfoxide, a method to treat with boron trichloride, boron tribromide or boron tribromide-dimethylsulfide complex in dichloromethane or 1,2-dichloroethane, a method to heat with pyridine hydrochloride, a method to treat with aluminum chloride, a method to treat with trifluoromethanesulfonic acid in the presence of thioanisole, a method to heat with 57% hydroiodic acid (here the reaction can be carried out in the presence of red phosphorus), a method to heat with 47% hydrobromic acid (here an auxiliary solvent such as acetic acid or dioxane may be used) and the like, and in particular it is preferable to use a method to reflux with 47% hydrobromicacid, which is efficient, inexpensive and simple.
Subsequently, 9-HC obtained in the above reaction is converted to CPT. Illustrative of methods for conversion are a method to lead 9-HC to the triflate (OSO2CF3: OTf) and to hydrogenolyze, a method to lead to the nonaflate (OSO2C4F9: ONf) and to hydrogenolyze, and a method to lead to the 1-phenyl-5-tetrazolyloxy derivative (OTz) and to hydrogenolyze and the like.
CPT can be obtained by any of the above CPT conversion methods, though in particular, from the point that CPT can be prepared by short steps in which the procedures are simple, reagents used are inexpensive, in actually the hydrogenolysis step inexpensive formic acid can be used of hydrogen gas as hydrogen source, and further heating and stirring can be made in a usual reaction apparatus, and from the point that each step proceeds in a good yield, it is preferred that 9-HC is treated with trifluoromethanesulfonyl chloride, trifluoromethanesulfonic acid anhydride, N-phenyl trifluoromethanesulfonimide or the like, leading to 9-trifluoromethanesulfonyloxycamptothecin (hereinafter referred to 9-OTfC) and further 9-OTfC is converted to CPT by hydrogenolysis, using palladium catalyst and formic acid as a hydrogen source, in the presence of a tertiary amine such as triethylamine or n-tributylamine.
In the following, the mode for carrying out the process for preparing CPT using 9-MC as a starting material in the invention is illustrated. However, the invention is not limited by this.
The figure below is the scheme for the conversion of 9-MC to CPT. 
The preferable embodiment for converting 9-MC to CPT comprises the following three steps:
1. the preparation step for 9-hydroxycamptothecin (9-HC);
2. the preparation step for 9-trifluoromethanesulfonyloxycamptothecin (9-OTfC);
3. the preparation step for camptothecin (hydrogenolysis of 9-OTfC).
To illustrate in more detail, specifically, in step 1 9-methoxycamptothecin (9-MC) is suspended in 47% hydrobromic acid, degassed under reduced pressure and heated under stirring after displacement by argon gas to give 9-HC. The amount used for 47% hydrobromic acid is in the range of 10 ml to 100 ml based on 1 g, preferably in the range of 15 ml to 25 ml. Temperature for heating is in the range of 100xc2x0 C. to 180xc2x0 C., preferably in the range of 160xc2x0 C. to 180xc2x0 C. Further, as to the reaction period, it is in the range of 1 hr to 24 hr, and heating for 3-4 hr is preferred.
9-MC, starting material, may be used without particular purification.
Further in this step, other known methods generally used in hydrolysis of aromatic methoxyl group can also be used.
In step 2, the above 9-HC was added with 1.0-5.0 equivalents of N-phenyl trifluoromethanesulfonimide, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic acid anhydride in the presence of a base using N,N-dimethylformamide, dichloromethane or chloroform as a solvent, and was reacted at ice-cooling to 100xc2x0 C. for 0.5-3 hr to give 9-OTfC. This reaction is preferably carried out in an inactive gas atmosphere such as argon gas. The starting material, 9-HC, may be used after isolation as it is, or an appropriately purified material by means such as column chromatography, recrystallization or reprecipitation may be used.
Illustrative of the base are organic bases such as triethylamine, n-butylamine, pyridine and N,N-dimethylaminopyridine, or alkaline metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Preferably, 1.5-3.5 equivalent amounts of N-phenyl trifluoromethanesulfonimide is used in the presence of 3.0-7.0 equivalents of triethylamine using N,N-dimethylformamide as solvent and heated at 50xc2x0 C. to 60xc2x0 C. for 0.5-1 hr to give 9-OTfC almost quantitatively. Further, as a trifluoromethanesulfonylating agent, the solvent such as dichloromethane or chloroform is preferable in case of use of trifluoromethanesulfonyl chloride or trifluoromethanesulfonic acid anhydride.
In step 3, 9-OTfC is added with formic acid as a hydrogen source in N,N-dimethylformamide as a solvent using palladium catalyst in the presence of base, stirred under argon gas atmosphere at 40xc2x0 C.-80xc2x0 C. for 1-18 hr, and hydrogenolyzed to give CPT. In this case, addition of molecular sieve 3 xc3x85 (MS3 xc3x85) can accelerate the reaction.
The base includes, for example, a tertiary amine such as triethylamine or n-tributylamine, and can be used in the range of 3-20 equivalents. Formic acid can be used in the range of 2-10 equivalents. Illustrative of the palladium catalyst are, for example, palladium acetate (Pd(OAc)2)-triphenylphosphine (Ph3P), palladium acetate-1,1xe2x80x2-bis(diphenylphsphino)ferrocene (DPPF), palladium acetate-tri-n-butylphosphine (n-Bu3P), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) and dichlorobis (triphenylphosphine)palladium (PdCl2(PPh3)2). The palladium catalyst can be used in the range of 4-50 mole %. In case of palladium acetate, phosphine ligand is added in the range of 8-100 mole %. Further, in the presence of the palladium catalyst the reaction can be carried our using N,N-dimethylformamide as a solvent, potassium carbonate as a base and borane-dimethylamine complex as a hydrogen source.
Preferably, as a palladium catalyst, palladium acetate in 3-6 mole % and triphenylphosphine in 6-12 mole %, or dichlorobis (triphenylphosphine) palladium in 5-15 mole % is used, added with triethylamin as the base in 3-14 equivalents and formic acid in 1.5-7 equivalents, and desirably reacted under an inactive gas atmosphere such as argon gas at near 60xc2x0 C. for 2-6 hr.
In this hydrogenolysis step, after triflate forming reaction, 9-OTfC can be used without isolation, or an appropriately purified material by means such as column chromatographic method or recrystallization can be used.
Further, as for the starting compound, the intermediate compound and the target compound, their stereoisomers, optical isomers, tautomeric isomers and the like are involved.